The long-term experimental objective of this competitive renewal is to evaluate the functional role of chemokine and chemokine receptors in contributing to neurologic disease and repair following infection with a neurotropic murine coronavirus, mouse hepatitis virus (MHV). Infection of susceptible mice with MHV reproducibly results in acute encephalitis followed by a chronic demyelinating disease characterized clinically by ascending hind-limb paralysis and histologically by mononuclear cell infiltration into the central nervous system (CNS) accompanied by white matter destruction. Due to the similarities in clinical and histologic disease between MHV-induced demyelination and the human demyelinating disease Multiple Sclerosis (MS), the MHV system is considered an excellent model in which to study the underlying pathological mechanisms contributing to human demyelinating diseases such as MS. Similar to MS, both T cells and macrophages are thought to be important in contributing to white matter destruction. In addition, chemokine and chemokine receptors are expressed within the CNS of MS patients as well as MHV-infected mice suggesting a role in promoting inflammation. We have successfully determined that the majority of chemokines and chemokine receptors exhibit important and non-redundant roles in participating in host defense and demyelination in response to MHV infection by regulating lymphocyte and macrophage accumulation within the CMS. The present proposal seeks to understand the underlying mechanisms by which the T cell chemoattractant CXCL10 modulates T cell infiltration into the CMS and influences the ability of the damaged CNS to remyelinate. To this end, experiments will determine if CXCL10 selectively recruits GD4+ T cells into the CNS as well as influencing T cell effector functions. In addition, studies will define how chronic CXCL10 expression suppresses the ability of the CNS to undergo remyelination through suppression of growth factors as well as chemokines necessary for oligodendrocyte progenitor cells to proliferate and positionally migrate within white matter tracts thus contributing to remyelination. Together, these studies will extend our current understanding of how chemokines and their receptors control CNS inflammation, demyelination, and ultimately repair. Further, the data obtained from these experiments may identify potential targets for therapeutic treatment of humans with MS as well as other inflammatory diseases.